REVIEW
Allergy immunotherapy across the life
cycle to promote active and healthy ageing:
from research to policies
An AIRWAYS Integrated Care Pathways (ICPs) programme item (Action Plan B3 of the
European Innovation Partnership on active and healthy ageing) and the Global Alliance
against Chronic Respiratory Diseases (GARD), a World Health Organization GARD
research demonstration project
M. A. Calderon
1, P. Demoly
2, T. Casale
3, C. A. Akdis
4, C. Bachert
5, M. Bewick
6, B. M. Bilò
7, B. Bohle
8, S. Bonini
9,
A. Bush
1, D. P. Caimmi
2, G. W. Canonica
10, V. Cardona
11, A. M. Chiriac
12, L. Cox
13, A. Custovic
1, F. De Blay
14,
P. Devillier
15, A. Didier
16, G. Di Lorenzo
17, G. Du Toit
18, S. R. Durham
19, P. Eng
20, A. Fiocchi
21, A. T. Fox
22,
R. Gerth van Wijk
23, R. M. Gomez
24, T. Haathela
25, S. Halken
26, P. W. Hellings
27, L. Jacobsen
28, J. Just
29,
L. K. Tanno
30,31,32, J. Kleine‑Tebbe
33, L. Klimek
34, E. F. Knol
35, P. Kuna
36, D. E. Larenas‑Linnemann
37,38,
A. Linneberg
39,40,41, M. Matricardi
42, H. J. Malling
43, R. Moesges
44, J. Mullol
45, A. Muraro
46, N. Papadopoulos
47,
G. Passalacqua
48, E. Pastorello
49, O. Pfaar
50,51,52, D. Price
53,54,55, P. Rodriguez del Rio
56, R. Ruëff
57, B. Samolinski
58,
G. K. Scadding
59,60, G. Senti
61, M. H. Shamji
62,63, A. Sheikh
64, J. C. Sisul
65, D. Sole
66, G. J. Sturm
67,68, A. Tabar
69,
R. Van Ree
70, M. T. Ventura
71, C. Vidal
72, E. M. Varga
73, M. Worm
74, T. Zuberbier
74and J. Bousquet
31,75,76,77,78*Abstract
Allergic diseases often occur early in life and persist throughout life. This life‑course perspective should be considered
in allergen immunotherapy. In particular it is essential to understand whether this al treatment may be used in old
age adults. The current paper was developed by a working group of AIRWAYS integrated care pathways for airways
diseases, the model of chronic respiratory diseases of the European Innovation Partnership on active and healthy
ageing (DG CONNECT and DG Santé). It considered (1) the political background, (2) the rationale for allergen immu‑
notherapy across the life cycle, (3) the unmet needs for the treatment, in particular in preschool children and old age
adults, (4) the strategic framework and the practical approach to synergize current initiatives in allergen immunother‑
apy, its mechanisms and the concept of active and healthy ageing.
Keywords: Allergen immunotherapy, EIP on AHA, AIRWAYS ICPs, Rhinitis, Asthma, Ageing
© The Author(s) 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Background
Allergic diseases often occur early in life and persist
throughout life. This life-course perspective should
be considered in allergen immunotherapy (AIT). In
particular it is essential to understand whether this
immunological treatment may be used in old age adults.
The current paper was developed by a working group
of AIRWAYS integrated care pathways (ICPs for airways
diseases), the model of chronic respiratory diseases of the
European Innovation Partnership on active and healthy
ageing (DG CONNECT and DG Santé) to develop the
concept of AIT across the life cycle and propose a
strate-gic framework to be tested.
Open Access
*Correspondence: [email protected]
78 CHRU, 371 Avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex
5, France
AIRWAYS integrated care pathways
The political background
Active and healthy ageing (AHA) is a major societal
chal-lenge, common to all populations. Ageing, together with
gender, socio-economic and other forms of inequalities
(
https://www.equalityhumanrights.com/en/equality-act/
protected-characteristics
), is an under-appreciated cause
of poor health, which can have an adverse impact on
eco-nomic development [
1
]. To tackle the burden of ageing
in the European Union (EU), the European Commission
launched the European Innovation Partnership (EIP) on
AHA within its innovation policy [
2
]. The EIP on AHA is
proposing a novel approach [
2
] that may be of great
ben-efit to the economic consequences of the demographic
changes in Poland. EIPs aim to enhance EU
competi-tiveness and tackle societal challenges through research
and innovation. They will address weaknesses in the EU
research and innovation (e.g. under-investment,
frag-mentation and duplication), which complicate the
dis-covery or exploitation of knowledge and may ultimately
prevent the entry of innovations into the market place.
EIP on AHA pursues a triple win for Europe:
• To enable EU citizens to lead healthy, active and
independent lives while ageing.
• To improve the sustainability and efficiency of social
and health care systems.
• To boost and improve the competitiveness of the
markets for innovative products and services,
responding to the ageing challenge at both EU and
global level, thus creating new opportunities for
busi-nesses.
ICPs for chronic respiratory diseases (AIRWAYS ICPs)
have been selected as a model for Action Plan B3 of the
EIP on AHA Strategic Implementation Plan [
3
,
4
]. The
goals of AIRWAYS ICPs are to launch a collaboration to
develop multi-sectoral care pathways for chronic
respira-tory diseases in European countries, regions and beyond
in association with the World Health Organization
(WHO) Global Alliance against chronic Respiratory
Dis-eases (GARD research demonstration project) [
5
]. There
are several ongoing actions among which:
• A synergy paper in press.
• A twinning for rhinitis in the elderly accepted
yester-day by the EU.
• An App and a tablet for rhinitis and asthma deployed
in 20 countries which received funding from private
sources and the EU Development and Structural
Funds [
6
–
10
].
• The scaling up strategy [
11
].
Prenatal and early-life events play a fundamental role
in health and on the development of non-communicable
diseases (NCDs) and AHA [
12
]. The Polish Presidency of
the EU Council targeted chronic respiratory diseases in
children to promote AHA [
13
]. It has been recognized
that the prevention and early diagnosis and treatment
of chronic respiratory diseases have a positive impact on
child development and health-related quality of life and
markedly contribute to an active and healthy childhood
as well as AHA. Therefore, the development of new tools
has been proposed for the early recognition and
improve-ment of treatimprove-ment for these conditions.
Respiratory allergies across the life cycle
IgE-mediated allergic diseases were defined by the World
Allergy Organization [
14
] and include allergic rhinitis
[
15
], allergic asthma [
16
], atopic dermatitis (AD) [
17
] and
food allergy. However, IgE-mediated allergy is not always
involved in the symptoms of these diseases [
18
–
21
]
including non-allergic rhinitis, and non-allergic asthma.
Respiratory allergic diseases (asthma and
rhinoconjunc-tivitis) are amongst the most common diseases worldwide
[
16
]. They affect all age groups and rank first in Europe.
The burden of these allergic diseases is substantial [
22
,
23
] since they often impair social life as well as school
and work performances [
15
,
24
,
25
]. Many patients are
untreated or uncontrolled (despite treatment) [
26
], remain
under-diagnosed and often do not receive adequate
treat-ment. These factors all contribute to poor disease control.
Allergic diseases often start early in life and tend to
persist across the life cycle, from infancy to the elderly.
This is especially true with asthma or rhinitis, which may
cause problems in individuals over 65 years of age [
27
].
Longitudinal birth cohort studies have shown sequential
events leading to upper and lower respiratory allergies
[
28
,
29
]. They start with weak sensitizations to a limited
number of allergen components followed by strong and/
or new sensitizations to varying allergen sources
depend-ing on the region of the world [
30
–
34
]. However, in a
large number of patients, sensitization does not change
over time and is fully developed in pre-school children
[
29
,
32
,
35
]. Moreover, the allergic march is uncommon
[
36
]. The escalation of sensitization parallels with the
clinical expression of the allergic disease. Genuine
sensi-tizers (either for food- or inhalant-related allergens) tend
to appear early in life, whereas specific IgE to
pan-aller-gens appear later [
37
].
Cohort studies following participants into middle age
have indicated that several factors, including childhood
asthma, low or impaired lung function at an early age
as well as atopy are risk factors for chronic obstructive
pulmonary disease (COPD) [
38
,
39
]. In asthma, allergic
sensitization was associated with worsening of
health-related quality of life [
40
] in the elderly, with a high
mor-tality risk due to under-diagnosis, under-treatment and
comorbidity [
41
]. First-time exposure to an occupational
allergen in any context (e.g. during apprenticeship) is
indeed a period of increased risk of developing
work-related respiratory allergic diseases such as asthma and
allergic rhinitis [
42
]. For example, occupational cleaners
are associated with an increased risk of developing both
asthma and self-reported COPD [
43
]. Established
occu-pational asthma may persist in spite of complete allergen
avoidance.
Over the past five decades, an “epidemic” of
aller-gic diseases and asthma has been observed globally in
children and adults [
5
]. The expected epidemic wave of
asthma and rhinitis in elderly adults remains an
insuffi-ciently recognized problem [
44
–
46
]. In Europe, over 20%
of adults suffer from allergic rhinitis and over 5% from
asthma [
15
,
47
]. These patients are now reaching the age
of 65 and a new health challenge in elderly people will be
to understand, detect and manage them. The importance
of AIT in these patients needs to be better defined, tested
and included in health policy making for the elderly [
13
].
Since we are entering an era of rapidly increasing
elderly people, and considering that asthma and rhinitis
usually commence during childhood or adulthood, both
diseases represent an emerging public health concern in
all age populations [
48
,
49
].
Rationale of allergy immunotherapy across the life
cycle in AIRWAYS ICPs
Allergy and allergen immunotherapy scope
Immunotherapy for IgE-mediated allergic diseases,
referred to as AIT, has entered a new era [
50
–
53
]. It is
characterized by: (1) thorough clinical development
pro-grammes leading to full registration and standardization
of products; (2) better understanding of the functions
of the immune system; (3) development of new
prod-ucts and routes to improve efficacy and safety; and (4)
harmonized clinical practice parameters based on both
evidence-based medicine and clinical experience. AIT
includes both allergen- and non-allergen-containing
therapeutics and is fully supported by the Polish
Presi-dency of the Council of the EU [
13
] and the Finnish
Allergy Plan [
27
,
54
]. Although dosing is now established
for some major allergens [
55
,
56
], mixing of allergens is
still a matter of debate and the selection of the allergen in
some polysensitized patients may still be difficult.
AIT induces immune tolerance
The goals for AIT are to control the symptoms of patients
who are unable to cope with their disease using optimal
pharmacotherapy [
9
,
57
,
58
]. Ultimately, AIT aims to
induce immune tolerance so that after its
discontinua-tion, there are persistent therapeutic benefits [
59
,
60
].
Whereas the early effects of AIT are probably related to
basophil/mast cell down-regulation, AIT produces an
early and transient inflammatory cell down-regulation
and a transient to long-lasting T cell tolerance [
61
,
62
].
This “tolerance” response is mainly mediated by IL-10,
TGF-β and other suppressive factors causing immune
deviation towards a more balanced T regulatory cell
response that leads to the observed suppression of
cytokines from allergen-specific Th1 and Th2 cells [
26
,
63
]. AIT also induces allergen-specific IL-10-producing
memory B regulatory cells, which seem to be responsible
for specific IgG4 production. Furthermore, AIT is
asso-ciated with the suppression of total IgE, allergen-specific
IgE, increases in allergen-specific blocking IgG
4anti-bodies [
64
,
65
], a decrease in both tissue mast cells and
eosinophil numbers [
66
] and the degree of activation.
AIT efficacy and safety
Clinical efficacy and safety of AIT for allergic asthma and
allergic rhinoconjunctivitis for the most relevant allergen
sources have been documented in well-powered
rand-omized controlled trials, at least for specific products.
Different systematic reviews and meta-analyses of
stud-ies in adults and children have confirmed efficacy for
many relevant allergen sources [
67
–
71
]. However, some
reviews were critical about AIT although certain
criti-cisms were raised [
72
]. AIT improves disease-specific
quality of life [
73
,
74
]. Follow-up studies after the
discon-tinuation of AIT have demonstrated a carry-over effect
which can last for up to 12 years after its cessation [
69
,
75
], but these studies are hampered by a high rate of drop
outs and the effectiveness of these long-lasting effects
needs more attention. AIT is thus a disease-modifying
intervention (the only one currently available) with the
potential of altering the allergic march [
76
,
77
]. Double
blind randomized controlled studies are currently
ongo-ing in children allergic to grass pollens [
78
] and house
dust mite to assess the potential prevention of asthma
(EudraCT 2012-005678-76) (Table
1
). It has been
sug-gested that AIT is cost-effective although more
informa-tion is needed [
53
,
79
,
80
].
Unmet needs
1. Tolerance to AIT in very young children Considering
that children born to atopic parents are at
consider-able increased risk of sensitization to common
envi-ronmental allergens [
81
], it is important to establish
the possible preventive role of AIT in reducing
sen-sitization (primary prevention) to any allergens when
given at infancy although the first results are
incon-clusive [
82
,
83
] or difficult to interpret [
84
].
2. When to start AIT in preschool children The
dem-onstration of a progressive molecular-spreading
process in allergic rhinitis [
30
] has provided the
rationale for an early allergen-specific
immunologi-cal intervention [
85
]. In this respect, studies on a
‘secondary allergen immuno-prophylaxis’ may be
targeted to children who are already sensitized to
airborne allergens but still asymptomatic. The
on-going allergic immune response is likely to be more
susceptible of being suppressed in the first, weaker,
pre-clinical monomolecular stages, rather than in
the polymolecular clinical stages. It is also plausible
that AIT will have a greater efficacy if started
imme-diately after the disease onset rather than, as usual,
years later. This concept of ‘early AIT’ should be
tested in properly designed prospective trials [
85
].
The results of the EU programme on Mechanisms
of the Development of ALLergy (MeDALL) have
improved the stratification of allergic preschool
children for diagnosis, prognosis and AIT [
28
,
29
].
Multi-morbidity, co-existing allergic diseases (such
as atopic eczema, allergic rhinitis and asthma) [
86
]
and/or IgE polysensitisation are markers of clinical
disease and disease persistence. For the first time
ever, MeDALL is proposing a scientific answer for
the initiation of AIT in pre-school children as it has
found that the vast majority of those with
multi-morbidities will have persistent allergic conditions
[
33
,
87
]. This finding has the potential to guide
physi-cians to consider starting AIT early in life and this
might lead to a greater expected efficacy to modify
the course of allergy. Moreover, allergy with
poly-sensitisation to birch pollen [
32
], cat or dog [
31
],
or peanut (Asarnoj, in preparation) at age four can
predict the onset and/or persistence of rhinitis and
asthma at 16 years. The MeDALL results have been
confirmed in patient cohorts [
88
,
89
]. It is therefore
suggested that preschool children with asthma and
rhinitis already sensitized may be considered as
can-didates for AIT.
3. Clinical tools to evaluate AIT There is a high degree
of clinical and methodological heterogeneity among
the endpoints in clinical studies on AIT, for both
SCIT (sub-cutaleous AIT) and SLIT (sublingual
AIT). At present, there are no commonly accepted
standards for defining the optimal outcome
parame-ters to be used for both primary and secondary
end-points [
90
]. A Task Force of the European Academy
of Allergy and Clinical Immunology (EAACI)
Immu-notherapy Interest Group evaluated the currently
used outcome parameters in different RCTs and
pro-vided recommendations for the optimal endpoints in
future AIT trials for allergic rhinoconjunctivitis.
Rec-ommendations for nine domains of clinical outcome
measures were made and recommended a
homo-geneous combined symptom and medication score
(CSMS) was recommended as a primary outcome
[
90
]. New ICT-based technology is likely to
consid-erably change patient reported outcomes (PROs) for
AIT during clinical trials and daily practice [
6
,
7
,
91
].
PROs should be adapted to the age groups.
Caregiv-ers are less able than children to accurately assess
response to treatment with available tools. A simple
pediatric-specific tool to assess efficacy in allergic
rhinitis trials in children is needed [
92
–
95
]. In older
adults, very few studies have investigated PROs, but
visual analogue scales appear to be of interest [
92
,
96
,
97
].
4. Stratification of patients allowing precision
medi-cine Precision medimedi-cine is a medical model
aim-ing to deliver customized healthcare—with medical
decisions, practices, and/or products tailored to the
individual patient. AIT has a unique immunological
rationale, since the approach is tailored to the
spe-cific IgE sensitization of an individual. It modifies the
natural course of the disease as it aims to have a
per-sistent efficacy after completion of treatment. In this
perspective, AIT can be considered a prototype of
precision medicine [
98
]. Biomarkers associated with
e-health, combined with a clinical decision support
system (CDSS), might change the scope of AIT.
5. Relevant immune mechanisms Several immune
changes have been associated with AIT. However,
the most relevant immune mechanisms leading
to clinical successful AIT have not yet been
identi-fied. This might be due to different administrations
of AIT, different allergens, different products, etc.
Deciphering the relevant immune mechanisms is
of the upmost importance to further improve
treat-ment protocols, finding relevant biomarkers, and to
improve the composition of AIT products.
6. Biomarkers Biomarkers in allergic diseases and
asthma are of great importance and a large body of
Table 1 Types of biomarkers for AIT
Identification and validation of biomarkers assessing the probability of response to treatment of AIT before it is initiated
Identification and validation of biomarkers assessing the safety of AIT before it is initiated
Identification and validation of biomarkers confirming the efficacy of AIT in patients receiving AIT (short and long term)
Identification and validation of biomarkers predicting the long‑term effects of AIT before it is stopped
Identification and validation of biomarkers predicting the relapse of symptoms when AIT is stopped
research has been initiated [
98
]. The identification of
biomarkers is based on systems biology approaches
combining transcriptomics, proteomics, epigenetics
and metabolomics in large patient cohorts. Two
EU-funded projects are currently ongoing: U-BIOPRED
(IMI) in severe asthma [
99
–
101
] and MeDALL
(FP7) in allergy [
28
,
29
]. These projects will help to
identify biomarkers for AIT efficacy [
102
–
104
] and
safety, and to better establish the personalized
medi-cine approach [
105
]. The following issues should be
addressed (Table
1
):
7. IgE sensitization profiles Combinatorial analysis has
shown that the IgE sensitization profiles to grass
pol-len in children with hay fever are very
heterogene-ous at the molecular level [
34
,
106
,
107
]. This high
heterogeneity is important in a scenario of
preci-sion medicine. Accordingly, a classification of
dif-ferent categories of match and mismatch between
the molecular profiles of IgE sensitization and the
molecular profile of an AIT preparation has been
illustrated [
106
]. Studies are needed to evaluate
the putative impact of matched or mismatched IgE
between the sensitization profile and the
molecu-lar composition of the AIT preparation used in the
individual patient. Moreover, recent studies in over
1300 Italian children with seasonal allergic rhinitis
have shown the importance of component-resolved
diagnosis (CRD) on the prescription of AIT against
pollens [
108
]. Molecular diagnosis with marker
allergens is nowadays a promising diagnostic step in
poly-sensitized individuals and it is essential to
dis-tinguish the primary sensitizers and “true” reactions
from cross-reactivity caused by pan-allergens.
AIT efficacy may be predicted by the IgE profile
[
102
,
109
,
110
], but more data are needed.
8. AIT in older adults The role of AIT for the treatment
of allergic diseases in old age should be considered.
The research agenda must include not only well
pow-ered randomized controlled trials in this age group
but also specific research on the immune response,
time of onset of allergic disease (since childhood,
adult life or late-onset in life), comorbidities, safety
and cost-benefits of AIT.
9. AIT in pregnancy Allergic diseases such as asthma
and allergic rhinitis constitute a significant burden
among women of childbearing age and those who
are pregnant. The continuation of AIT during
preg-nancy appears safe [
111
]. Available studies do not
however show a convincing reduction in the
devel-opment of atopy in offspring from the administration
of AIT during pregnancy [
111
].
10. AIT for skin allergy A Cochrane review found limited
evidence that AIT may be effective for people with
atopic eczema [
112
]. The treatments used in these
trials were not associated with an increased risk of
local or systemic reactions. Future studies should
use high quality allergen formulations with a proven
track record in other allergic conditions and should
include PROs as key outcome measures.
11. SCIT versus SLIT Direct head-to-head
compari-sons of subcutaneous AIT (SCIT) versus sublingual
AIT (SLIT; tablets or drops) are limited [
113
] and
have generated contradictory results [
114
].
Simi-larly, indirect comparisons are inconsistent. This is
perhaps due to the lack of standardization of
clini-cal outcomes measured, dosages, heterogeneous
compositions, schedules and duration of treatment
[
67
]. There are very few SCIT studies that meet the
CONSORT criteria for publication and most are
not ITT analyses [
115
,
116
]. Moreover, efficacy and
safety have been shown only for some SLIT and
SCIT products. Comparisons should also be made
between products [
117
]. For some allergen sources
and age groups, effective SLIT or SCIT doses have
not been established [
69
].
12. AIT in polysensitized individuals Although AIT has
proven efficacy in large, robust clinical trials in
pri-marily polysensitized patients [
55
,
69
], more work is
required to determine whether single-allergen source
and multi-allergen source AIT also produce distinct
immune and clinical responses in monosensitized
and polysensitized patients [
118
]. The currently
available literature suggests that when the clinically
relevant allergen has been identified, AIT is effective
also in polysensitized patients [
118
].
13. Ideal schedule for sublingual AIT For some allergen
extract preparations, efficacy (SLIT with pollen) has
been shown with a pre-coseasonal administration
schedule, as opposed to other extracts for which
the year-round perennial schedule is recommended.
This has implications for the cost-benefit analysis as
well as for adherence. Until direct comparative
stud-ies between dosing are conducted, it is speculative
as to which schedule adherence might ultimately be
enhanced.
14. Duration of AIT International harmonisation on the
criteria used to determine the duration of AIT is
necessary. Adherence to treatment, route of
admin-istration, cost, allergen source, patient’s
comorbidi-ties and polysensitisation are all factors that should
be considered as well as the age of onset of AIT. It is
usually recommended to perform AIT for a duration
of 3 years, but data are insufficient.
15. Cost-effectiveness A health technology assessment
study funded by the UK National Institute for Health
Research Health Technology Assessment (NIHR
HTA) programme concluded that a benefit from
both SCIT and SLIT compared with placebo has
been consistently demonstrated. However, the extent
of this effectiveness in terms of clinical benefit is
unclear. Both SCIT and SLIT may be cost-effective
compared with AIT from around 6 years (threshold
of £20,000–30,000 per QALY) [
80
]. In a US study
based on Florida Medicaid data on allergic rhinitis
patients from poverty environments, the cut-even
point for SCIT was already reached at 3 months
[
119
]. The results of this study are restricted to
the US model and the population treated. Further
research is urgently needed to establish the
compara-tive effeccompara-tiveness of SCIT compared with SLIT and
to provide more robust cost-effectiveness estimates
[
71
,
80
]. Although it is not accepted by regulators
yet, cost-effectiveness might be best shown in more
real-life trial designs.
16. Novel forms of AIT Recombinant allergens [
74
,
120
,
121
] or the chemical and molecular modification of
allergens and the use of different routes of
adminis-tration of AIT should aim to facilitate its use for a
wider scope of allergic diseases. However, these new
options should be assessed in the context of the
patient’s convenience and adherence to treatment,
long-term efficacy, disease-modifying effects and
cost-benefits. Biologics added to AIT may be
effec-tive for some (anti-IgE [
122
–
124
]) but not all targets
(anti-IL-4 [
125
]). In this case, an economic
evalua-tion is needed to stratify the patients.
Proposal to integrate AIT in AIRWAYS ICPs
Strategic framework
Integration and dissemination of international and
national clinical practice guidelines are part of the process
of ICPs. ICPs differ from practice guidelines as they are
utilized by a multidisciplinary team and focus on the
qual-ity and coordination of care. Clinicians are free to exercise
their own professional judgment as appropriate. An ICP
is intended to act as a guide to treatment for the single
patient. Any alteration to the practice identified within
the ICP algorithm should be noted as a variance.
Vari-ance analysis can be used to amend the ICP itself if, for a
group of patients, the practice consistently differs from the
pathway.
ICPs form all or part of the clinical record,
docu-ment the care given, and facilitate the evaluation of
out-comes for continuous quality improvement. They should
empower patients and their health and social care givers.
Objectives
The aims of AIRWAYS ICPs are to:
• Better understand the role of AIT across the life
cycle, particularly in preschool children (prevention
and treatment) and in the elderly.
• Increase the awareness of the impact of AIT across
the life cycle to promote AHA.
• Better stratify patients who benefit the most from
AIT in all age groups.
• Launch a collaboration to develop care pathways for
chronic respiratory allergic diseases integrating AIT
in European countries and regions in the frame of
AIRWAYS ICPs.
• Follow and implement actions and plans suggested
by this integrated collaboration.
• Provide evidence for regulatory decisions.
• Propose new policies in the EU. AIRWAYS ICPs and
AIT to be incorporated in Action Plan B3 of the EIP
on AHA.
• Follow and implement actions and plans suggested
by this integrated collaboration, which are to be
endorsed by national health authorities.
Approach
This project aims to synergize current initiatives in AIT,
allergic diseases and healthy ageing, as part of the
AIR-WAYS ICPs programme.
A multi-sectoral approach is proposed. It will include
all targeted groups such as (1) the general
popula-tion (patients, parents, teachers, media, patient’s
asso-ciations), (2) primary care (general practitioners and
general pediatricians, pharmacists, nurses) and (3)
sec-ondary care (allergists, organ and other allergy specialists
including pediatrics, ENT, internal medicine,
derma-tology, respiratory, clinical immunologists, and patient
associations).
Partners will include (1) relevant academic consortia
(MeDALL, GA
2LEN, ARIA, PRACTALL), (2) relevant
academic societies (both national and international),
(3) manufacturers of allergy diagnostics and allergen
preparations.
A stratification of patients across the life cycle using
novel biomarkers, e-health and CDSS.
The integration of modern e-health tools should be
promoted. Indeed, the use of electronic information and
communications technologies in health is rising rapidly
in the developing world, offering essential improvements
in the management of respiratory allergies. This
tech-nology will allow better disease control and monitoring,
promoting AIT compliance. These will include: (1) the
Sentinel Network of GA
2LEN and MACVIA-LR, (2) the
MASK model of MACVIA-LR, including novel CDSS [
7
,
126
] and (3) the currently available applications of certain
investigators and pharmaceutical companies.
A stepwise framework is favoured. The AIRWAYS ICPs
group will collect data, make proposals and then
dissemi-nate and evaluate actions.
Step 1—Data collection We are aiming to create a
port-folio providing all available current published data on
the subject. As an example, the most recent documents
provided by EAACI (AIT guidelines and consensus
reports), ARIA (rhinitis and asthma guidelines), and
WAO (SLIT guidelines) will be included and deposited
in the EIP on AHA repository.
Step 2—Proposals and actions We will summarize and
select the best feasible proposals to integrate AIT in
AIRWAYS ICP across the EU. As an example, the best
windows of intervention for AIT in children and all
possible interventions later in life will be scrutinized.
Step 3—Dissemination and follow-up Use of the pro
-posals will be promoted as much as possible and
sur-veyed. As an example, a module will be created for
presentations at national and EU meetings, as well as
for e-learning.
Step 4—Changes in policies Policies for senior citizens
in countries should reflect the epidemiologic wave of
the still unrecognized allergic diseases in the elderly.
Novel approaches in health systems and
reimburse-ment policies are needed for AIT in well-stratified
patients using modern technologies. The effectiveness,
cost-effectiveness and safety of such policies will need
to be established.
Abbreviations
AHA: active and healthy ageing; AIRWAYS ICPs: integrated care pathways for airway diseases; ARIA: allergic rhinitis and its impact on asthma; AIT: allergen immunotherapy; CDSS: clinical decision support system; CONSORT: consoli‑ dated standards of reporting trials; COPD: chronic obstructive pulmonary dis‑ ease; CRD: chronic respiratory diseases; DG: Directorate General; EIP on AHA: European Innovation Partnership on active and healthy ageing; EU: European Union; GA2LEN: Global Allergy and Asthma European Network (FP6); GARD:
WHO global alliance against chronic respiratory diseases; ICP: integrated care pathway; IL: interleukin; MACVIA‑LR: contre les MAladies Chroniques pour un VIeillissement Actif (fighting chronic diseases for active and healthy ageing); MASK: MACVIA‑ARIA Sentinel NetworK; MeDALL: Mechanisms of the Develop‑ ment of ALLergy (FP7); MOH: Ministry of Health; NCD: non‑communicable disease; PRACTALL: PRACTicing ALLergology; PRO: patient reported outcome; RCT: randomized control trial; SCIT: subcutaneous immunotherapy; SLIT: sub‑ lingual immunotherapy; Th: T helper cell; U‑BIOPRED: Unbiased BIOmarkers in PREDiction of respiratory disease outcomes; WHO: World Health Organization.
Authors’ contributions
JB drafted the paper. All authors are members of the ARIA and/or MACVIA‑ ARIA working groups and read and commented the paper. All authors read and approved the final manuscript.
Author details
1 National Heart and Lung Institute, Royal Brompton Hospital NHS, Imperial
College London, London, UK. 2 Unité d’allergologie, Département de
Pneumologie et AddictologieHôpital Arnaud de Villeneuve, CHRU de Montpellier, Sorbonne Universités, UPMC Paris 06, UMR‑S 1136, IPLESP, Equipe EPAR, 75013 Paris, France. 3 University of South Florida Morsani College
of Medicine, Tampa, FL, USA. 4 Christine Kühne Center for Allergy Research
and Education (CK‑CARE), Swiss Institute of Allergy and Asthma Research (SIAF)University of Zurich, Davos, Switzerland. 5 Upper Airways Research
Laboratory (URL), ENT Department, University Hospital Ghent, Ghent, Belgium.
6 iQ4U consultants Ltd, London, UK. 7 Allergy Unit, Department of Internal
Medicine, University Hosp Ospedali Riuniti, Ancona, Italy. 8 Department
of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
9 Second University of Naples and IFT‑CNR, Rome, Italy. 10 Allergy and Respira‑
tory Diseases Clinic, DIMI, University of Genoa, IRCCS AOU San Martino‑IST, Genoa, Italy. 11 Allergy Section, Department of Internal Medicine, Hospital
Universitari Vall d’Hebron, Barcelona, Spain. 12 Division of Allergy, Hôpital
Arnaud de Villeneuve, Department of Pulmonology, University Hospital of Montpellier, Montpellier ‑ UPMC Univ Paris 06, UMRS 1136, Equipe ‑ EPAR ‑ IPLESP, Sorbonne Universités, Paris, France. 13 Nova Southeastern University,
Ft. Lauderdale, FL, USA. 14 Allergy Division, Chest Disease Department,
University Hospital of Strasbourg, Strasbourg, France. 15 University Versailles
Saint‑Quentin and Clinical Pharmacology Unit, UPRES EA 220, Department of Airway Diseases, Foch Hospital, Suresnes, France. 16 Respiratory Diseases
Department, Rangueil‑Larrey Hospital, Toulouse, France. 17 Dipartimento
BioMedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), University of Palermo, Palermo, Italy. 18 Guy’s and St. Thomas’ NHS Trust, Kings College,
London, UK. 19 Allergy and Clinical Immunology Section, National Heart
and Lung Institute, Imperial College London, London, UK. 20 Department
of Pediatric Pulmonology and Allergy, Children’s Hospital, Aarau, Switzerland.
21 Division of Allergy, Department of Pediatrics, Bambino Gesù Pediatric
Hospital, Vatican City, Rome, Italy. 22 King’s College London Allergy Academy,
London, UK. 23 Section of Allergology, Department of Internal Medicine,
Erasmus Medical Center, Building Rochussenstraat, Rotterdam, The Netherlands. 24 Unidad Alergia and Asma, Hospital San Bernardo, Salta,
Argentina. 25 Skin and Allergy Hospital, Helsinki University Hospital, Helsinki,
Finland. 26 Hans Christian Andersen Children’s Hospital, Odense University
Hospital, Odense, Denmark. 27 Clinical Department of Otorhinolaryngology,
Head and Neck Surgery, University Hospitals Leuven, KU Leuven, Louvain, Belgium. 28 Allergy Learning and Consulting, Secretary Immunotherapy
Interest Group EAACI, Copenhagen, Denmark. 29 Allergology Department,
Centre de l’Asthme et des Allergies, Hôpital d’Enfants Armand‑Trousseau, INSERM, UMR_S 1136, Sorbonne Universités, UPMC Univ Paris, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Equipe EPAR, Paris, France.
30 Hospital Sírio Libanês, São Paulo, Brazil. 31 University Hospital of Montpellier,
Montpellier, France. 32 UPMC Paris 06, UMR‑S 1136, IPLESP, Equipe EPAR,
Sorbonne Universités, Paris, France. 33 Allergy and Asthma Center Westend,
Outpatient Clinic and Clinical Research Center, Ackermann, Hanf, & Kleine‑Tebbe, Berlin, Germany. 34 Center for Rhinology and Allergology,
German Society for Otorhinolaryngology HNS, Wiesbaden, Germany.
35 Departments of Immunology and Dermatology/Allergology, University
Medical Center Utrecht, Heidelberglaan, Utrecht, The Netherlands. 36 Medical
University of Lodz, Lodz, Poland. 37 ARIA, Mexico, DF, Mexico. 38 AAAAI, Hospital
Médica Sur, Mexico, DF, Mexico. 39 Research Centre for Prevention and Health,
The Capital Region of Denmark, Copenhagen, Denmark. 40 Department
of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark.
41 Department of Clinical Medicine, Faculty of Health and Medical Sciences,
University of Copenhagen, Copenhagen, Denmark. 42 Pediatric Pneumology
and Immunology, Charité Medical University, Berlin, Germany. 43 Danish
Allergy Centre, Allergy Clinic, Gentofte University Hospital, Hellerup, Denmark.
44 IMSIE, Klinikum der Universität zu Köln A. ö. R., Cologne, Germany. 45 Unitat
de Rinologia i Clínica de l’Olfacte, ENT Department, Hospital Clínic, Clinical and Experimental Respiratory Immunoallergy, IDIBAPS, CIBERES, Barcelona, Catalonia, Spain. 46 Department of Women and Child Health, Food Allergy
Referral Centre Veneto Region, Padua General University Hospital, Padua, Italy.
47 Allergy Unit, 2nd Pediatric Clinic, University of Athens, Athens, Greece. 48 Allergy and Respiratory Diseases, IRCCS San Martino‑IST, Univesity of Genoa,
Genoa, Italy. 49 ASST Grande Ospedale Metropolitano Niguarda, P.zza Ospedale
Maggiore, Milan, Italy. 50 Department of Otorhinolaryngology, Head and Neck
Surgery, Universitätsmedizin Mannheim, Mannheim, Germany. 51 Medical
Faculty Mannheim, Heidelberg University, Heidelberg, Germany. 52 Center
for Rhinology and Allergology, Wiesbaden, Germany. 53 Division of Applied
Health Sciences, Primary Care Respiratory Medicine, Academic Primary Care, University of Aberdeen, Aberdeen, Scotland, UK. 54 Research in Real Life (RiRL),
Oakington, Cambridge, UK. 55 Optimum Patient Care Ltd, Singapore,
Singapore. 56 Allergy Section, Hospital Infantil Universitario Niño Jesús, Madrid,
University, Munich, Germany. 58 Department of Prevention of Environmental
Hazards and Allergology, Medical University of Warsaw, Warsaw, Poland.
59 Royal National Throat, Nose and Ear Hospital, London, UK. 60 University
College London, London, UK. 61 Clinical Trials Center, University Hospital
of Zurich, Zurich, Switzerland. 62 Immunomodulation and Tolerance Group,
Allergy and Clinical Immunology, Inflammation, Repair and Development Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK. 63 MRC and Asthma UK Centre in Allergic
Mechanisms of Asthma, London, UK. 64 Asthma UK Centre for Applied
Research, Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. 65 SLAAI, Asuncion, Paraguay. 66 Programa de
Pòs‑Graduação em Pediatria e Ciências Aplicadas à Pediatria, Departamento de Pediatria EPM, UNIFESP, São Paulo, Brazil. 67 Department of Dermatology
and Venerology, Medical University of Graz, Graz, Austria. 68 Allergy Outpatient
Clinic Reumannplatz, Vienna, Austria. 69 Servicio de Alergologia, Complejo
Hospitalario de Navarra, Pamplona, Spain. 70 Departments of Experimental
Immunology and Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 71 Unit of Geriatric Immunoaller‑
gology, Interdisciplinary Department of Medicine, University of Bari Medical School, Bari, Italy. 72 Allergy Department, Complejo Hospitalario Universitario
de Santiago de Compostela, Santiago de Compostela, Spain. 73 Respiratory
and Allergic Disease Division, Department of Paediatrics, Medical University of Graz, Graz, Austria. 74 Allergie‑Centrum‑Charité, Klinik für Dermatologie,
Venerologie und Allergologie, Charité‑Universitätsmedizin Berlin, Berlin, Germany. 75 Contre les MAladies Chroniques pour un VIeillissement Actif en
Languedoc‑Roussillon, European Innovation Partnership on Active and Healthy Ageing Reference Site, Paris, France. 76 INSERM, VIMA, U1168,
Ageing and Chronic Diseases, Epidemiological and Public Health Approaches, Paris, France. 77 UVSQ, UMR‑S 1168, Université Versailles St‑Quentin‑en‑Yve‑
lines, Versailles Cedex, France. 78 CHRU, 371 Avenue du Doyen Gaston Giraud,
34295 Montpellier Cedex 5, France.
Acknowledgements
None.
Competing interests
The authors declare that they have no competing interests.
Funding
European Innovation Partnership on Active and Healthy Ageing Reference Site MACVIA‑France, European Structural and Development Funds of Region Languedoc Roussillon.
Received: 25 September 2016 Accepted: 2 November 2016
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